Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: UNC Lineberger Comprehensive Cancer Center
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests a new treatment to fight certain types of cancer in adults. The treatment aims to improve how the body targets and kills cancer cells. Researchers will collect samples to see how well the treatment works and lasts in the body.
Is the treatment ATLCAR.CD30 Cells a promising treatment for testicular cancer?Yes, ATLCAR.CD30 Cells, which are a type of CAR T-cell therapy, show promise for treating testicular cancer. They can target and kill cancer cells that have the CD30 marker, and they can also attack nearby cancer cells that don't have this marker. This makes them a strong candidate for treating aggressive forms of testicular cancer.1281012
What safety data is available for CD30 CAR T-Cell therapy in testicular cancer?The safety data for CD30 CAR T-Cell therapy, while not specific to testicular cancer, can be inferred from general CAR T-Cell studies. CAR T-Cell therapies, including those targeting CD30, have shown potential in treating hematologic malignancies with some success. However, they are associated with risks such as cytokine release syndrome, neurotoxicity, and 'on-target off-tumor' effects, where healthy cells expressing the target antigen may also be affected. Strategies to mitigate these risks, such as pharmacologic interventions and suicide genes, are under investigation. CD30 CAR T-Cells have been noted to spare CD30+ hematopoietic stem cells while targeting lymphoma cells, suggesting a level of safety in targeting CD30. Overall, while promising, CAR T-Cell therapies require careful management of potential toxicities.456711
What data supports the idea that CD30 CAR T-Cells for Testicular Cancer is an effective treatment?The available research shows that CD30 CAR T-Cells have demonstrated antitumor activity against embryonal carcinomas, a type of testicular cancer, in both laboratory and animal studies. These cells were able to target and kill cancer cells that express the CD30 marker, as well as nearby cancer cells that do not express this marker, through a special interaction. This suggests that CD30 CAR T-Cells could be a promising treatment for testicular cancer, especially for aggressive types that are difficult to treat with standard therapies.238910
Do I have to stop taking my current medications for the trial?The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
Eligibility Criteria
Adults over 18 with Nonseminomatous Germ Cell Tumors (NSGCT) who've had at least one prior treatment can join. They must show tumor growth or elevated cancer markers after high-dose chemo. Pregnant women, those breastfeeding, and individuals with active HIV, HTLV, hepatitis B or C are excluded.Inclusion Criteria
I am 18 years old or older.
My cancer is a type of germ cell tumor that is not seminoma.
Treatment Details
The trial is testing ATLCAR.CD30 Cells combined with Cyclophosphamide and Fludarabine in patients with NSGCT. It's a phase 2 study to see if modified T cells from the patient's blood can fight cancer more effectively when combined with antibodies.
1Treatment groups
Experimental Treatment
Group I: ATLCAR.CD30Experimental Treatment3 Interventions
Single Group Assignment: Subjects with Nonseminomatous Germ Cell Tumors who meet eligibility criteria for cellular therapy.
Find a clinic near you
Research locations nearbySelect from list below to view details:
Lineberger Comprehensive Cancer Center at University of North Carolina, Chapel HillChapel Hill, NC
Loading ...
Who is running the clinical trial?
UNC Lineberger Comprehensive Cancer CenterLead Sponsor
University Cancer Research Fund at Lineberger Comprehensive Cancer CenterCollaborator
References
CD30 antigen in embryonal carcinoma and embryogenesis and release of the soluble molecule. [2022]The expression, serological detection, and possible functional role of the CD30 antigen in Hodgkin's disease and anaplastic large cell lymphoma is well documented. In embryonal carcinoma (EC), the expression of this cytokine receptor has been demonstrated only by immunohistology. Because the CD30 monoclonal antibody Ki-1 was found to cross-react with an unrelated molecule, we examined by in situ hybridization testicular germ cell neoplasms for the presence of CD30-specific transcripts. CD30 mRNA was detectable in the tumor cells of 9 of 9 cases of EC or mixed germ cell tumors with an EC component but in no other nonlymphoid tumors. Thus, the CD30 transcript expression pattern proved to be identical to the immunostaining pattern seen with the CD30-specific monoclonal antibody Ber-H2. By Northern blot analysis, CD30 transcripts could be demonstrated in the EC cell line Tera-2. Employing a highly sensitive second generation sandwich enzyme-linked immunosorbent assay, we could detect the soluble CD30 molecule in 8 of 8 sera from patients with a diagnosis of EC but not in 8 of 10 sera from patients with other testicular germ cell tumors. In fetal tissue, no CD30-expressing germ cells or epithelial cells could be observed. Thus, the cellularly expressed CD30 marker for testicular neoplasms of EC type. Moreover, the serum levels of soluble CD30 antigen seem to be a promising parameter for monitoring patients with EC.
CD30 and its ligand: possible role in regulation of teratoma stem cells. [2019]Like the oocyte, the cells of the early embryo, and primordial germ cells, human teratocarcinoma stem cells are pluripotent, capable of giving rise to a wide range of somatic and extraembryonic tissues. Growth factors which regulate the growth of multipotent stem cells in the mouse have been identified, but none of these have been shown conclusively to have similar effects on human or primate multipotent stem cells. CD30 is a member of the tumour necrosis factor receptor superfamily with a restricted pattern of tissue distribution, limited to immune cells, decidual tissue, and human embryonal carcinoma: in common with other embryonal carcinoma markers, CD30 is found in foci of cells in a sub-population of seminomas. CD30 ligand is a transmembrane protein, structurally related to tumour necrosis superfamily members TNF alpha, TNF beta, and CD40. CD30 ligand is expressed by T and B lymphocytes, macrophages, and a variety of normal haematopoietic cells and tumours derived from them, and exerts pleiotropic effects on normal and malignant lymphoid cells, including death, differentiation, or cell division. Studies on cultured cell lines derived from human embryonal carcinomas and yolk sac carcinomas confirm CD30 expression in the former but not the latter, and show that CD30 expression is down-regulated during stem cell differentiation in vitro. Transcripts for CD30 ligand are found at highest levels in yolk sac carcinoma cell lines, but are also found in embryonal carcinoma. CD30 ligand protein is detected in yolk sac carcinoma and nullipotent embryonal carcinoma cell lines. Exogenous CD30 ligand has no effect on multipotent human stem cell growth in vitro. However, the receptor-ligand pair may function in autocrine regulation of embryonal carcinoma stem cells. CD30 and its ligand are candidate stem cell identity factors, juxtacrine regulators whose sole function is to identify a cell's position in a developmental hierarchy.
Prognostic implications of CD30 expression in extranodal natural killer/T-cell lymphoma according to treatment modalities. [2022]Extranodal natural killer/T-cell lymphoma (NKTCL) has aggressive behaviors and poor clinical outcomes. A monomethyl auristatin E-conjugated anti-CD30 antibody (brentuximab vedotin) was recently introduced to treat CD30-positive lymphomas. Thus we investigated the clinicopathological features and prognostic implications of CD30 expression in 72 patients with NKTCL. CD30-positive cases, defined as cases with CD30 expression in more than 1%, 5% and 25% of tumor cells as cut-off values (COVs), accounted for 40 (56%), 27 (38%) and 16 (22%) cases of NKTCL, respectively. CD30 expression was significantly higher in large/anaplastic cell-predominant NKTCL than in small/medium cell-predominant cases. CD30-positive NKTCL showed better responses to non-anthracycline-based therapy. CD30-positive NKTCL with COV of 25% showed a lower rate of relapse. Moreover, in patients treated with non-anthracycline-based chemotherapy, CD30 positivity with COV of 5% was significantly and independently associated with longer overall survival. CD30 may be useful as a prognostic factor and therapeutic target in NKTCL.
Seatbelts in CAR therapy: How Safe Are CARS? [2022]T-cells genetically redirected with a chimeric antigen receptor (CAR) to recognize tumor antigens and kill tumor cells have been infused in several phase 1 clinical trials with success. Due to safety concerns related to on-target/off-tumor effects or cytokine release syndrome, however, strategies to prevent or abate serious adverse events are required. Pharmacologic therapies; suicide genes; or novel strategies to limit the cytotoxic effect only to malignant cells are under active investigations. In this review, we summarize results and toxicities of investigations employing CAR redirected T-cells, with a focus on published strategies to grant safety of this promising cellular application.
Gene-modified T-cell therapy using chimeric antigen receptors for pediatric hematologic malignancies. [2017]Chimeric antigen receptor (CAR) is the generic name for synthetic T cell receptors redirected to tumor-associated antigens. Most CARs consist of an ectodomain (scFv or ligand), a hinge region, a transmembrane domain, and signaling endodomains derived from one or two co-stimulatory molecules (CD28, 4-1BB, etc) and from a CD3-ζ chain. CD19-targeted CAR T cell therapy has achieved major success in the treatment of B cell malignancies. CD19 CAR-T cells elicited complete remission in 70-90% of adult and pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). CD19 CAR T cell therapy from allogeneic donors including third party donors is a potential option for B-cell malignancies. CAR T cell therapies for myeloma, acute myeloid leukemia, and T-cell leukemia are still under development. Our group is currently preparing a phase I study of CD19 CAR T cell therapy in pediatric and young adult patients with ALL using a non-viral gene transfer method, the piggyBac-transposon system.
Shared target antigens on cancer cells and tissue stem cells: go or no-go for CAR T cells? [2017]Label="INTRODUCTION" NlmCategory="BACKGROUND">Adoptive therapy with chimeric antigen receptor (CAR) T cells redirected towards CD19 produces remissions of B cell malignancies, however, it also eradicates healthy B cells sharing the target antigen. Such 'on-target off-tumor' toxicity raises serious safety concerns when the target antigen is also expressed by tissue stem cells, with the risk of lasting tissue destruction. Areas covered: We discuss CAR T cell targeting of activation antigens versus lineage associated antigens on the basis of recent experimental and animal data and the literature in the field. Expert commentary: Targeting an activation associated antigen which is transiently expressed by stem cells seems to be safe, like CAR T cells targeting CD30 spare CD30+ hematopoietic stem and progenitor cells while eliminating CD30+ lymphoma cells, whereas targeting lineage associated antigens which increase in expression during cell maturation, like folate receptor-β and CD123, is of risk to destruct tissue stem cells.
Toxicity and management in CAR T-cell therapy. [2023]T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR). Most notably, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors. However, CAR T cells also have the capacity to elicit expected and unexpected toxicities including: cytokine release syndrome, neurologic toxicity, "on target/off tumor" recognition, and anaphylaxis. Theoretical toxicities including clonal expansion secondary to insertional oncogenesis, graft versus host disease, and off-target antigen recognition have not been clinically evident. Abrogating toxicity has become a critical step in the successful application of this emerging technology. To this end, we review the reported and theoretical toxicities of CAR T cells and their management.
CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30+ and CD30- Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions. [2020]Tumor antigen heterogeneity limits success of chimeric antigen receptor (CAR) T-cell therapies. Embryonal carcinomas (EC) and mixed testicular germ cell tumors (TGCT) containing EC, which are the most aggressive TGCT subtypes, are useful for dissecting this issue as ECs express the CD30 antigen but also contain CD30-/dim cells. We found that CD30-redirected CAR T cells (CD30.CAR T cells) exhibit antitumor activity in vitro against the human EC cell lines Tera-1, Tera-2, and NCCIT and putative EC stem cells identified by Hoechst dye staining. Cytolytic activity of CD30.CAR T cells was complemented by their sustained proliferation and proinflammatory cytokine production. CD30.CAR T cells also demonstrated antitumor activity in an in vivo xenograft NOD/SCID/γcnull (NSG) mouse model of metastatic EC. We observed that CD30.CAR T cells, while targeting CD30+ EC tumor cells through the CAR (i.e., antigen-dependent targeting), also eliminated surrounding CD30- EC cells in an antigen-independent manner, via a cell-cell contact-dependent Fas/FasL interaction. In addition, ectopic Fas (CD95) expression in CD30+ Fas- EC was sufficient to improve CD30.CAR T-cell antitumor activity. Overall, these data suggest that CD30.CAR T cells might be useful as an immunotherapy for ECs. Additionally, Fas/FasL interaction between tumor cells and CAR T cells can be exploited to reduce tumor escape due to heterogeneous antigen expression or to improve CAR T-cell antitumor activity. Cancer Immunol Res; 6(10); 1274-87. ©2018 AACR.
The potential of brentuximab vedotin, alone or in combination with current clinical therapies, in the treatment of testicular germ cell tumors. [2020]Testicular germ cell tumors (TGCTs) are the commonest tumors in young men. With the advancement of chemotherapies, most TGCTs are successfully cured, even when diagnosed at an advanced and metastatic stage. However, a proportion of often young patients, median age 35-40, with advanced disease are not cured and will inevitably die. Therefore, there is an unmet need in this small population of young patients who are candidates for experimental approaches. We investigated a new therapeutic option for this group of patients, aiming to significantly improve their outcome. In recent years, many targeted therapies have been developed which demonstrated high efficacy and low toxicity. Brentuximab vedotin, a monomethyl auristatin E conjugated CD30 antibody, targets CD30 to kill cancer cells. As a large proportion of TGCTs express CD30, in particular embryonal carcinomas, we investigated in vitro the efficacy of brentuximab vedotin in treating TGCTs as a single therapy and in combination with commonly used chemotherapy drugs. We determined CD30 expression levels in 12 TGCT cell lines, including three cisplatin resistant sublines. In general, the efficiency of cancer cell inhibition by brentuximab vedotin correlates with CD30 expression, but there were some exceptions. We also determined the efficacy of brentuximab vedotin in combination with commonly used chemotherapy drugs and found synergistic/additive effects with etoposide, paclitaxel and SN-38. However, cisplatin, the most commonly used chemotherapy drug in TGCT treatment, exhibited antagonism and we showed that cisplatin selectively kills CD30 positive cells. We also found that certain agents, which have been reported to induce CD30 expression in other human malignant diseases, including DNA demethylation drugs, methotrexate and CD30 ligands, were unable to enhance CD30 expression or brentuximab vedotin efficacy in TGCT cells. This study will help to design clinical trials using brentuximab vedotin for the treatment of TGCTs, either as a single agent or in combination with current clinical therapies.
A new immunotherapy strategy targeted CD30 in peripheral T-cell lymphomas: CAR-modified T-cell therapy based on CD30 mAb. [2022]Chimeric antigen receptor T-cell immunotherapy (CAR-T) has shown remarkable efficacy in treating tumors of lymphopoietic origin. Herein, we demonstrate an effective CAR-T cell treatment for recurrent and malignant CD30-positive peripheral T-cell lymphomas (PTCL) has been demonstrated. The extracellular fragment gene sequences of CD30 were obtained from tumor tissues of PTCL patients and cloned into a plasmid vector to express the CD30 antigen. The CD30 targeting single-chain antibody fragment (scFv) was obtained from CD30-positive monoclonal hybridoma cells, which were obtained from CD30 antigen immunized mice. After a second-generation of CAR lentiviral construction, CD30 CAR T cells were produced and used to determine the cytotoxicity of this construct toward Karpas 299 cells. The results of CD30 CAR T-mediated cell lysis show that 9C11-2 CAR T cells could significantly promote the lysis of CD30-positive Karpas 299 cells in both LDH and real-time cell electronic sensing (RTCA) assays. In vivo data show that 9C11-2 CAR T cells effectively suppress the tumor growth in a Karpas 299 cell xenograft NCG mouse model. The CD30 CAR T cells exhibited an efficient cytotoxic effect after being co-cultured with the target cells and they also exhibited a significant tumor-inhibiting ability after being intravenously injected into PTCL xenograft tumors; these observations suggest that the new CD30 CAR-T cell may be a promising therapeutic candidate for cancer therapy.
Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. [2022]T cells expressing CD19-specific chimeric antigen receptors (CD19-CARs) have potent antileukemia activity in pediatric and adult patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (B-ALL). However, not all patients achieve a complete response (CR), and a significant percentage relapse after CD19-CAR T-cell therapy due to T-cell intrinsic and/or extrinsic mechanisms. Thus, there is a need to evaluate new CD19-CAR T-cell products in patients to improve efficacy. We developed a phase 1/2 clinical study to evaluate an institutional autologous CD19-CAR T-cell product in pediatric patients with relapsed/refractory B-ALL. Here we report the outcome of the phase 1 study participants (n = 12). Treatment was well tolerated, with a low incidence of both cytokine release syndrome (any grade, n = 6) and neurotoxicity (any grade, n = 3). Nine out of 12 patients (75%) achieved a minimal residual disease-negative CR in the bone marrow (BM). High disease burden (≥40% morphologic blasts) before CAR T-cell infusion correlated with increased side effects and lower response rate, but not with CD19-CAR T-cell expansion. After infusion, CD8+ CAR T cells had a proliferative advantage over CD4+ CAR T cells and at peak expansion, had an effector memory phenotype with evidence of antigen-driven differentiation. Patients that proceeded to allogeneic hematopoietic cell transplantation (AlloHCT) had sustained, durable responses. In summary, the initial evaluation of our institutional CD19-CAR T-cell product demonstrates safety and efficacy while highlighting the impact of pre-infusion disease burden on outcomes. This trial was registered at www.clinicaltrials.gov as #NCT03573700.
CD30 as a therapeutic target in adult haematological malignancies: Where are we now? [2023]CD30 is a transmembrane protein from the tumour necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms. CD30 is a particularly interesting treatment target because its levels are high in tumours but low in healthy tissues. Several therapeutic strategies targeting CD30 have been developed, including monoclonal antibodies, conjugated antibodies (combination of brentuximab vedotin with chemotherapy or immunotherapy), bispecific antibodies and cell and gene therapies, such as anti-CD30 CAR-T cells in particular. We briefly review the biology of CD30 which makes it a good therapeutic target, and we describe all of the anti-CD30 therapies that have emerged to date.